DESCRIPTION: (Principal Investigator's Abstract) Based on our continued development of powerful and rapid methodology for the study of reaction mechanisms, we propose to study the mechanisms for a series of important organic, organometallic, and bioorganic reactions. This includes coarctate reactions, conjugate additions to cuprates, olefin metathesis, additions of ketenes and phosphinidenes to alkenes, the enzymatic decarboxylation of orotate, the enzymatic cyclization of squalene oxide, and many others. The unique capabilities of our methodologies should significantly advance mechanistic understanding of these reactions. We also plan to extend our methodology by developing more robust probes of reaction mechanisms and isotope-effect probes of structure and intermolecular interactions. The health-relatedness of this work derives from its impact on the understanding of reactions important in the synthesis of medicinally important substances and reactions important in biosynthetic pathways.